Somatostatin and the "Small-For-Size" Liver.

"Small-for-size" livers arising in the context of liver resection and transplantation are vulnerable to the effects of increased portal flow in the immediate postoperative period. Increased portal flow is an essential stimulus for liver regeneration. If the rise in flow and stimulus for regeneration are excessive; however, liver failure and patient death may result. Somatostatin is an endogenous peptide hormone that may be administered exogenously to not only reduce portal blood flow but also offer direct protection to different cells in the liver. In this review article, we describe key changes that transpire in the liver following a relative size reduction occurring in the context of resection and transplantation and the largely beneficial effects that peri-operative somatostatin therapy may help achieve in this setting.

Somatostatin Therapy Improves Stellate Cell Activation and Early Fibrogenesis in a Preclinical Model of Extended Major Hepatectomy.

Liver resection treats primary and secondary liver tumors, though clinical applicability is limited by the remnant liver mass and quality. Herein, major hepatic resections were performed in pigs to define changes associated with sufficient and insufficient remnants and improve liver-specific outcomes with somatostatin therapy. Three experimental groups were performed: 75% hepatectomy (75H), 90% hepatectomy (90H), and 90% hepatectomy + somatostatin (90H + SST). Animals were followed for 24 h (N = 6) and 5 d (N = 6). After hepatectomy, portal pressure gradient was higher in 90H versus 75H and 90H + SST (8 (3-13) mmHg vs. 4 (2-6) mmHg and 4 (2-6) mmHg, respectively, p < 0.001). After 24 h, changes were observed in 90H associated with stellate cell activation and collapse of sinusoidal lumen. Collagen chain type 1 alpha 1 mRNA expression was higher, extracellular matrix width less, and percentage of collagen-staining areas greater at 24 h in 90H versus 75H and 90H + SST. After 5 d, remnant liver mass was higher in 75H and 90H + SST versus 90H, and Ki-67 immunostaining was higher in 90H + SST versus 75H and 90H. As well, more TUNEL-staining cells were observed in 90H versus 75H and 90H + SST at 5 d. Perioperative somatostatin modified portal pressure, injury, apoptosis, and stellate cell activation, stemming changes related to hepatic fibrogenesis seen in liver remnants not receiving treatment.

A novel and simple formula to predict liver mass in porcine experimental models.

A primary limitation in hepatic surgery is leaving a remnant liver of adequate size and function. Experimental models have been designed to study processes of liver injury and regeneration in this context, yet a formula to accurately calculate liver mass in an animal model is lacking. This study aims to create a novel and simple formula to estimate the mass of the native liver in a species of pigs commonly used in experimental liver surgery protocols. Using data from 200 male weanling Landrace-Large White hybrid pigs, multiple linear regression analysis is used to generate the formula. Clinical features used as variables for the predictive model are body mass and length. The final formula for pig liver mass is as follows: Liver mass (g) = 26.34232 * Body mass (kg) - 1.270629 * Length (cm) + 163.0076; R2 = 0.7307. This formula for porcine liver mass is simple to use and may be helpful in studies using animals of similar characteristics to evaluate restoration of liver mass following major hepatectomy.

Rare mutations in SLC12A1 and SLC12A3 protect against hypertension by reducing the activity of renal salt cotransporters.

OBJECTIVES: Screening for variants in SLC12A1 and SLC12A3 genes, encoding the renal Na:Cl (NCC) and Na:K:2Cl (NKCC2) cotransporters, respectively, in 3125 members of the Framingham Heart Study (FHS) revealed that carrying a rare mutation in one of these genes was associated with a significant reduction in blood pressure, in the risk of arterial hypertension, and of death due to cardiovascular disease. Because near 60% of the rare mutations identified have not been related to Bartter's or Gitelman's disease, the consequence of such mutations on cotransporter activity is unknown. METHODS: We used the heterologous expression system of Xenopus laevis oocytes, microinjected with wild-type or mutant NCC or NKCC2 cRNAs, to examine the effect of these inferred NCC and NKCC2 mutations on the cotransporters' functional properties. Cotransporter activity was defined as the diuretic-sensitive radioactive tracer uptake and response to known modulators was assessed. RESULTS: Basal NCC activity was significantly reduced in all NCC mutants and, excluding NCC-S186F, response to WNK3, WNK4, or intracellular chloride depletion was conserved. Similarly, basal activity was reduced in six out of nine NKCC2 mutants and response to WNK3 was maintained. No effect on protein expression was seen, except for NCC-S186F, which was significantly reduced. CONCLUSIONS: The rare NCC or NKCC2 mutations found in the FHS significantly reduced the basal activity of the cotransporters. This observation supports that even a small, but chronic reduction of NCC or NKCC2 function results in a lower blood pressure and decreased risk of hypertension in otherwise healthy individuals in the general population.

Renocortical mRNA expression of vasoactive factors during spironolactone protective effect in chronic cyclosporine nephrotoxicity.

We showed that spironolactone reduced structural damage and prevented renal dysfunction in chronic cyclosporine (CsA) nephrotoxicity. These findings evidenced an aldosterone renal vascular effect under this condition. To investigate aldosterone's role in modulating renal vascular tone, renocortical vasoactive pathways mRNA levels in chronic CsA nephrotoxicity as well as spironolactone's effect on renal function in acute CsA nephrotoxicity were evaluated. Two experimental sets were designed. For chronic nephrotoxicity, rats fed with low-sodium diet were divided into groups receiving vehicle, spironolactone (Sp), CsA, and CsA+Sp, for 21 days. Creatinine clearance, survival percentage, and renocortical mRNA levels of pro-renin, angiotensinogen (Ang), angiotensin receptors (AT(1A), AT(1B), and AT(2)), preproendothelin, endothelin receptors (ET(A), ET(B)), cyclooxygenase-2 (COX-2), and adenosine receptors (Ad(1), Ad(2A), Ad(2B), and Ad(3)) were analyzed. For acute nephrotoxicity, similar groups fed with a standard chow diet for 7 days were included. Serum potassium and sodium, glomerular filtration rate (GFR), and renal blood flow (RBF) were determined. In chronic model, CsA produced pro-renin and ET upregulation, altered adenosine receptors expression, and reduced Ang, AT(1A), AT(1B), ET(B), and COX-2 mRNA levels. Spironolactone protective effect in chronic nephrotoxicity was associated with prevention of pro-renin upregulation and increased AT(2), together with ET(B) reduction. In acute nephrotoxicity, spironolactone completely prevented GFR and RBF reduction induced by CsA. Our results suggest that aldosterone contributes to renal vasoconstriction observed in CsA nephrotoxicity and that renoprotection conferred by spironolactone was related to modification of renocortical vasoactive pathways expression, in which pro-renin normalization was the most evident change in chronic nephropathy. Finally, our data point to spironolactone as a potential treatment to reduce CsA nephrotoxicity in transplant patients.